Ketones asymmetric cyanosilylation

Scheme 6.85 Product range of the 73- and 74-catalyzed asymmetric cyanosilylation of ketones.

We began our synthesis by finding the optimum reaction conditions for the catalytic asymmetric cyanosilylation of ketone 28 (Table 1). Based on previous studies,30 the titanium complex of a D-glucose derived ligand (catalyst 32 or 33) generally gives (/ )-ketone cyanohydrins, which is required for a synthesis of natural fostriecin. 

Asymmetric cyanosilylation of ketones and aldehydes is important because the cyanohydrin product can be easily converted into optically active aminoalcohols by reduction. Moberg, Haswell and coworkers reported on a microflow version of the catalytic cyanosilylation of aldehydes using Pybox [5]/lanthanoid triflates as the catalyst for chiral induction. A T-shaped borosilicate microreactor with channel dimensions of 100 pm X 50 pm was used in this study [6]. Electroosmotic flow (EOF) was employed to pump an acetonitrile solution of phenyl-Pybox, LnCl3 and benzal-dehyde (reservoir A) and an acetonitrile solution of TMSCN (reservoir B). LuC13-catalyzed microflow reactions gave similar enantioselectivity to that observed in analogous batch reactions. However, lower enantioselectivity was observed for the YbCl3-catalyzed microflow reactions than that observed for the batch reaction (Scheme 4.5). It is possible that the oxophilic Yb binds to the silicon oxide surface of the channels. 

Finally, carbohydrate ligands of enantioselective catalysts have been described for a limited number of reactions. Bis-phosphites of carbohydrates have been reported as ligands of efficient catalysts in enantioselective hydrogenations [182] and hydrocyanations [183], and a bifunctional dihydroglucal-based catalyst was recently found to effect asymmetric cyanosilylations of ketones [184]. Carbohydrate-derived titanocenes have been used in the enantioselective catalysis of reactions of diethyl zinc with carbonyl compounds [113]. Oxazolinones of amino sugars have been shown to be efficient catalysts in enantioselective palladium(0)-catalyzed allylation reactions of C-nucleophiles [185]. 

Trost and coworkers developed a chiral zinc phenoxide for the asymmetric aldol reaction of acetophenone or hydroxyacetophenone with aldehydes (equations 62 and 63) . This method does not involve the prior activation of the carbonyls to silyl enol ethers as in the Mukaiyama aldol reactions. Shibasaki and coworkers employed titanium phenoxide derived from a phenoxy sugar for the asymmetric cyanosilylation of ketones (equation 64). 2-Hydroxy-2 -amino-l,l -binaphthyl was employed in the asymmetric carbonyl addition of diethylzinc , and a 2 -mercapto derivative in the asymmetric reduction of ketones and carbonyl allylation using allyltin ° . ... 

Although HCN also adds to these unsaturated bonds to afford cyanohydrins and a-amino nitriles, use of TMSCN instead of HCN provides an efficient and safer route to these compounds. Cyanosilylation with TMSCN is accelerated by acid and base catalysts. In recent years a variety of organic and inorganic compounds have been found to work as effective catalysts, and much attention has been devoted for the development of chiral catalysts for asymmetric cyanosilylation of aldehydes, ketones, and imines. 

Inoue et al. reported that a complex prepared from AlMes and peptide Schiff base 166 is available for asymmetric cyanosilylation of aldehydes (Scheme 10.239) [630]. The enantioselectivity observed is not as high, even with a stoichiometric amount of the complex (up to 71% ee). A more recent study by Snapper and Hoveyda has, however, revealed that a similar catalyst system using Al(()t-Pr) ), and peptide Schiff base 167 is quite effective in catalytic asymmetric cyanosilylation of both aromatic and aliphatic ketones (66->98%, 80-95% ee wifh 10-20 mol% of fhe catalyst) [631]. 

Scheme 124 Asymmetric cyanosilylation of ketones early in the syntheses of different members of the bisorbicillinoid family...

Tian SK, Hong R, Deng L (2003) Catalytic Asymmetric Cyanosilylation of Ketones with Chiral Lewis Base. J Am Chem Soc 125 9900... 

The asymmetric cyanosilylation of ketones is a challenge in terms of the catalyst efficiency and substrate generality, due to the decreased steric discrimination and the lower reactivity of ketones compared with aldehydes. 

Scheme 19.9 Asymmetric cyanosilylation of ketones catalysed by an Al-peptide complex.

Asymmetric cyanosilylation of ketones and aldehydes is highly important, since the cyanohydrin product can easily be converted into optically active aminoalcohols... 

Scheme 6.84 Typical silylated cyanohydrins prepared from various ketones under asymmetric 72-catalysis (cyanosilylation).

Figure 6.23 Proposed transition states of the asymmetric 72-catalyzed cyanosilylation of ketones describe two alternative mechanistic pathways for cooperative catalysis Addition via thiourea-bound ketone (TS 1, preferred) and addition via thiourea-bound cyanide (TS 2).

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

Our proposed transition state model for this catalytic enantioselective cyanosilylation of ketone is shown as 35.30a The titanium acts as a Lewis acid to activate the substrate ketone, while the phosphine oxide acts as a Lewis base to activate TMSCN. The intramolecular transfer of the activated cyanide to the activated ketone should give the ( )-cyanohydrin in high selectivity. The successful results described above clearly demonstrate the practicality of our asymmetric catalyst for cyanosilylation of ketones. 

Deng et al. later found that dimeric cinchona alkaloids such as (DHQ AQN (8, Scheme 6.6) and (DHQD PHAL (9, Scheme 6.7) - both well known as ligands in the Sharpless asymmetric dihydroxylation and commercially available - also catalyze the highly enantioselective cyanosilylation of acetal ketones with TMSCN... 

Thus, the asymmetric catalysis of cyanoethoxycarbonylation, cyanophosphoryla-tion, epoxidation of electron-deficient olefins, Michael reactions of malonates and (3-keto-esters, Strecker reaction of keto-imines, conjugate addition of cyanide to a, (3-unsaturated pyrrole amides, ring opening of meso aziridines with TMSCN and cyanosilylation of ketones (example shown below) have been successfully carried out using these complexes as asymmetric catalysts. 

---